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"Tian, Ni-ni"
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Lack of tumorigenesis and protumorigenic activity of human umbilical cord mesenchymal stem cells in NOD SCID mice
Background
The tumorigenesis of infused umbilical cord mesenchymal stem cells (UC-MSCs) is being preclinically evaluated.
Methods
We observed tumor formation in NOD SCID mice after a single subcutaneous injection of hUC-MSCs and the effect of these cells on tumor growth in tumor-bearing mice. Three generations (P5, P7, and P10) of hUC-MSCs (1 × 10
7
) from two donors (hUC-MSC1 and hUC-MSC2) were inoculated subcutaneously into NOD SCID mice. Subcutaneous transplantation models were established in NOD SCID mice with human cervical cancer HeLa cells (solid tumor) and human B cell lymphoma Raji cells (hematological tumor). Then, the animals were euthanized, gross dissection was performed, and tissues were collected. Various organs were observed microscopically to identify pathological changes and tumor metastasis.
Results
In the tumorigenesis experiment, no general anatomical abnormalities were observed. In the tumor promotion experiment, some animals in the HeLa groups experienced tumor rupture, and one animal died in each of the low- and medium-dose hUC-MSC groups. The results may have occurred due to the longer feeding time, and the tumor may have caused spontaneous infection and death. Pathological examination revealed no metastasis to distant organs in any group. In the Raji tumor model, some animals in each group experienced tumor rupture, and one animal in the medium-dose hUC-MSC group died, perhaps due to increased tumor malignancy. Thus, hUC-MSCs neither promoted nor inhibited tumor growth. No cancer cell metastasis was observed in the heart, liver, spleen, lungs, kidneys or other important organs, except that pulmonary venule metastasis was observed in 1 animal in the model group.
Conclusions
Injected hUC-MSCs were not tumorigenic and did not significantly promote or inhibit solid or hematological tumor growth or metastasis in NOD SCID mice.
Journal Article
The neutrophil-to-lymphocyte ratio is associated with all-cause and cardiovascular mortality among individuals with hypertension
Background
Identifying reliable prognostic markers is crucial for the effective management of hypertension. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential inflammatory marker linked to cardiovascular outcomes. This study aims to investigate the association of NLR with all-cause and cardiovascular mortality among patients with hypertension.
Methods
This study analyzed data from 3067 hypertensive adults in the National Health and Nutritional Examination Surveys (NHANES) from 2009 to 2014. Mortality details were obtained from the National Death Index (NDI). Restricted cubic spline (RCS) was deployed to visualize the association of the NLR with mortality risk. Weighted Cox proportional hazards models were employed to assess the independent association of NLR with mortality risk. Time-dependent receiver operating characteristic curve (ROC) analysis was conducted to access the predictive ability of NLR for survival. Mediation analysis was used to explore the indirect impact of NLR on mortality mediated through eGFR.
Results
Over a median 92.0-months follow-up, 538 deaths occurred, including 114 cardiovascular deaths. RCS analysis revealed a positive association between NLR and both all-cause and cardiovascular mortality. Participants were stratified into higher (> 3.5) and lower (≤ 3.5) NLR groups. Weighted Cox proportional hazards models demonstrated that individuals with higher NLR had a significantly increased risk of all-cause (HR 1.96, 95% confidence interval (CI) 1.52–2.52,
p
< 0.0001) and cardiovascular mortality (HR 2.33, 95% CI 1.54–3.51,
p
< 0.0001). Stratified and interaction analysis confirmed the stability of the core results. Notably, eGFR partially mediated the association between NLR and both all-cause and cardiovascular mortality by a 5.4% and 4.7% proportion, respectively. Additionally, the areas under the curve (AUC) of the 3-, 5- and 10- year survival was 0.68, 0.65 and 0.64 for all-cause mortality and 0.68, 0.70 and 0.69 for cardiovascular mortality, respectively.
Conclusion
Elevated NLR independently confers an increased risk for both all-cause and cardiovascular mortality in individuals with hypertension.
Journal Article
Hederagenin’s uric acid-lowering effects in hyperuricemic mice: Mechanistic insights from molecular docking and in vivo analysis
This study explored the uric acid-lowering effects of hederagenin (HD) through molecular docking analysis and a chronic hyperuricemia (HUA) mouse model. Molecular docking was performed to evaluate HD’s interactions key urate-regulating proteins, including xanthine oxidase (XOD), ABCG2, OAT1, URAT1, and GLUT9. To establish a chronic HUA model, mice were fed a yeast-adenine diet supplemented with potassium oxonate. The mice were randomly assigned to six groups: normal control, HUA model control, benzbromarone (BEN) group, and three HD treatment groups at doses of 50, 100, and 200 mg/kg. Serum uric acid (UA) levels, liver and kidney function indicators, XOD activity, and oxidative stress markers were assessed. Histopathological analyses of the liver and kidney were also conducted. In addition, gene and protein expression levels of urate transporters and inflammatory markers were assessed using RT-PCR and Western blotting. The results showed that HD interacts with XOD and urate transporters, significantly reducing serum UA levels and inhibiting XOD activity in HUA model. It also modulated the expression of urate transporter to enhance UA excretion. Moreover, HD protected liver and kidney function by reducing pro-inflammatory cytokine levels and inhibiting the TLR4/Myd88/NF-κB and NLRP3 signaling pathways. These findings suggest HD may serve as a promising therapeutic agent for lowing uric acid and preventing organ damage associated with HUA.
Journal Article
The interaction between sleep patterns and oxidative balance scores on the risk of cognitive function decline: Results from the national health and nutrition examination survey 2011–2014
Unhealthy sleep and exposures to oxidative factors are both associated with poor cognitive performance (PCP), but limited evidence has been found regarding the relationship between sleep patterns and oxidative factor exposures independently or jointly with the risk of PCP.
We analyzed data from 2249 adults aged ≥60 years in the National Health and Nutrition Examination Survey (NHANES) database (2011-2014). Self-reported questionnaires were used to collect data on sleep duration and sleep disorder, categorizing sleep duration into three groups based on responses: short (6 hours or less per night), normal (7-8 hours per night), or long (9 hours or more per night). Sleep disorder were categorized into two groups: sleep disorder, non-sleep disorder. Oxidative balance score (OBS) was calculated based on 20 oxidative stress exposures related to diet and lifestyle factors, with higher scores indicating greater antioxidant exposures. Survey-based multivariable adjusted regression analyses were conducted to examine the associations between sleep patterns or OBS alone and in combination with overall and PCP risks.
Compared to the normal sleep duration group, the long sleep duration group had a higher risk of PCP (DSST<34) (OR = 1.91, 95% CI = 1.05-3.48, P = 0.021); while OBS was negatively correlated with the risk of PCP (DSST<34) [Q4 vs Q1 (OR = 0.50, 95% CI = 0.29-0.92, P = 0.004)]. There was an interaction effect between sleep patterns (sleep duration, sleep disturbances) and OBS on PCP (DSST<34) (P = 0.002). Further stratified analysis showed that in individuals with normal sleep duration, long sleep duration, or no sleep disturbances, antioxidant exposures, compared to pro-oxidant exposures, reduced the risk of low cognitive function occurrence.
In older populations, unhealthy sleep patterns (especially excessive sleep duration) and low OBS alone or in combination increase the risk of cognitive decline. Healthy sleep and lifestyle habits rich in antioxidant factors are crucial for protecting cognitive function in older adults.
Journal Article
Effects and mechanisms of mUCMSCs on ovarian structure and function in naturally ageing C57 mice
Background
The ovaries are the core reproductive organs in women and are critical for maintaining normal reproductive function and endocrine system stability. An ageing C57 mouse model was used to evaluate the efficacy and mechanism of mouse umbilical cord mesenchymal stem cells (mUCMSCs) and to explore the mechanism by which mUCMSCs promote the antioxidant repair of mouse granulosa cells (mGCs).
Results
Eighteen-month-old C57 mice were randomly divided into a model group and a treatment group. At the same time, 2-month-old C57 mice were established as a young group (15 mice per group). The mice in the treatment group were injected via the tail vein with GFP-labelled mUCMSCs. The ovarian volume in ageing C57 mice was decreased, and there were no follicles at any stage. After mUCMSC transplantation, the mouse ovaries increased in size, follicles at various stages were observed in the cortex, and the antral follicle counts increased. The serum E2, AMH, and INH-B levels of mice in the treatment group were significantly higher than those of mice in the model control group (
P
< 0.05). mUCMSCs downregulated the expression of the autophagy-related gene LC3b and the apoptosis-related genes Bax and Caspase-3, upregulated the expression of SOD2 and the peroxidase gene PRDX IV, and reduced apoptosis rates and reactive oxygen species (ROS) levels in granulosa cells.
Conclusions
mUCMSCs play roles in promoting the repair of ageing ovaries by regulating immunity, anti-inflammatory responses and the PI3K-Akt signalling pathway.
Journal Article
Responses of Bacterial Communities in Arable Soils in a Rice-Wheat Cropping System to Different Fertilizer Regimes and Sampling Times
Soil physicochemical properties, soil microbial biomass and bacterial community structures in a rice-wheat cropping system subjected to different fertilizer regimes were investigated in two seasons (June and October). All fertilizer regimes increased the soil microbial biomass carbon and nitrogen. Both fertilizer regime and time had a significant effect on soil physicochemical properties and bacterial community structure. The combined application of inorganic fertilizer and manure organic-inorganic fertilizer significantly enhanced the bacterial diversity in both seasons. The bacterial communities across all samples were dominated by Proteobacteria, Acidobacteria and Chloroflexi at the phylum level. Permutational multivariate analysis confirmed that both fertilizer treatment and season were significant factors in the variation of the composition of the bacterial community. Hierarchical cluster analysis based on Bray-Curtis distances further revealed that bacterial communities were separated primarily by season. The effect of fertilizer treatment is significant (P = 0.005) and accounts for 7.43% of the total variation in bacterial community. Soil nutrients (e.g., available K, total N, total P and organic matter) rather than pH showed significant correlation with the majority of abundant taxa. In conclusion, both fertilizer treatment and seasonal changes affect soil properties, microbial biomass and bacterial community structure. The application of NPK plus manure organic-inorganic fertilizer may be a sound fertilizer practice for sustainable food production.
Journal Article
Role of EZH2-mediated H3K27me3 in placental ADAM12-S expression: implications for fetoplacental growth
Background
Enhancer of zeste homolog 2 (EZH2)-mediated histone 3 lysine 27 trimethylation (H3K27me3) is a transcription silencing mark, which is indispensable for cell lineage specification at the early blastocyst stage. This epigenetic repression is maintained in placental cytotrophoblasts but is lifted when cytotrophoblasts differentiate into syncytiotrophoblasts. However, the physiological impact of this lift remains elusive. Here, we investigated whether lifting EZH2-mediated H3K27me3 during syncytialization upregulates the expression of a short secretory isoform of a disintegrin and metalloprotease 12 (ADAM12-S), a well-recognized placenta-derived protease that cleaves insulin-like growth factor binding protein 3 to increase insulin-like growth factor (IGF) bioavailability for the stimulation of fetoplacental growth. The transcription factor and the upstream signal involved were also explored.
Methods
Human placenta tissue and cultured primary human placental cytotrophoblasts were utilized to investigate the role of EZH2-mediated H3K27me3 in ADAM12-S expression and the associated transcription factor and upstream signal during syncytialization. A mouse model was used to examine whether inhibition of EZH2-mediated H3K27me3 regulates placental ADAM12-S expression and fetoplacental growth.
Results
EZH2 and ADAM12 are distributed primarily in villous cytotrophoblasts and syncytiotrophoblasts, respectively. Increased ADAM12-S expression, decreased EZH2 expression, and decreased EZH2/H3K27me3 enrichment at the
ADAM12
promoter were observed during syncytialization. Knock-down of EZH2 further increased ADAM12-S expression in trophoblasts. Syncytialization was also accompanied by increased STAT5B expression and phosphorylation as well as its enrichment at the
ADAM12
promoter. Knock-down of STAT5B attenuated ADAM12-S expression during syncytialization. Epidermal growth factor (EGF) was capable of inducing ADAM12-S expression via stimulation of STAT5B expression and phosphorylation during syncytialization. Mouse studies revealed that administration of an EZH2 inhibitor significantly increased ADAM12-S levels in maternal blood and fetoplacental weights along with decreased H3K27me3 abundance and increased ADAM12-S expression in the placenta.
Conclusions
Lifting EZH2-mediated H3K27me3 increases ADAM12-S expression during syncytialization with the participation of EGF-activated STAT5B, which may lead to elevation of ADAM12-S level in maternal blood resulting in increased IGF bioavailability for the stimulation of fetoplacental growth in pregnancy. Our studies suggest that the role of EZH2-mediated H3K27me3 may switch from cell lineage specification at the early blastocyst stage to regulation of fetoplacental growth in later gestation.
Journal Article
Restirring and Reheating Effects on Microstructural Evolution of Al–Zn–Mg–Cu Alloy during Underwater Friction Stir Additive Manufacturing
Friction stir additive manufacturing (FSAM) can be potentially used for fabricating high-performance components owing to its advantages of solid-state processing. However, the inhomogeneous microstructures and mechanical properties of the build attributed to the complex process involving restirring and reheating deserve attention. This study is based on the previous research of the underwater FSAMed 7A04 aluminum alloy and adopts a quasi in situ experimental method, i.e., after each pass of the underwater FSAM, samples were taken from the build for microstructural observation to investigate the restirring and reheating effects on microstructural evolution during the underwater FSAM. Fine-grain microstructures were formed in the stir zone during the single-pass underwater FSAM. After restirring, the grain size at the bottom of the overlapping region decreased from 1.97 to 0.87 μm, the recrystallization degree reduced from 74.0% to 29.8%, and the initial random texture transformed into a strong shear texture composed of the C 110<11¯0>. After reheating, static recrystallization occurred in the regions close to the new additive zones, increasing the grain size and recrystallization degree. This study not only revealed the microstructural evolution during the underwater FSAM but also provided a guideline for further optimization of the mechanical properties of the Al–Zn–Mg–Cu alloy build.
Journal Article
Investigating the relationship between blood metabolites and diabetic retinopathy using two-sample mendelian randomization and in vivo validation
We addressed fundamental questions about the influence of metabolites on the development of Diabetic retinopathy (DR), and explored the related pathological mechanism. Genome-wide association study (GWAS) database data for metabolites and DR were used to perform Mendelian randomization (MR) studies. The inverse variance weighting (IVW) was chosen as the primary analysis method. Sensitivity analysis was conducted using MR-PRESSO, leave-one-out and Cochran’s Q test. Confounding factors were eliminated to ensure robustness. We also conducted metabolic pathway analysis. In vivo experimental validation was conducted using Sprague Dawley rats. The serum metabolites of the DR group rats and normal group rats were examined to evaluate the MR results. The screen identified eighteen metabolites associated with DR risk, twelve of which were known components. Seven metabolites were positively correlated with DR risk, while five could reduce it. Eight metabolites associated with proliferative DR (PDR) risk were identified, four of which are known components. Three of these were positively associated with PDR risk and one metabolite reduced PDR risk. Additionally, two possible metabolic pathways involved in the biological mechanism of DR were identified. The ELISA results showed that the serum levels of isoleucine and 4-HPA were significantly increased in DR rats, while the level of inosine was decreased. This study offers novel insights into the biological mechanisms underlying DR. Metabolites that are causally linked to DR may serve as promising biomarkers and therapeutic targets.
Journal Article